An in-depth understanding of genetic and biochemical regulation in mammalian cells is necessary to the understanding of maturation, malignancy, and aging. The regulation of two critical biochemical pathways, those of purine and pyrimidine biosynthesis, will be studied in Chinese hamster cells grown in culture to obtain this fundamental knowledge. This will be done by the characterization of mutants of Chinese hamster cells, some of which were isolated in this laboratory during the previous granting period, which show apparent defects in regulation of these two pathways. Mutants will be analyzed regarding the nature of their response to nutrilites, inhibitors and analogues added to their growth medium. Parameters such as growth, alteration in intracellular nucleotide concentrations, changes in levels of particular enzymes, and alterations in mRNA transcription and translation will be examined. Assignment of genes defective in mutants to specific human chromosomes will be undertaken by the technique of human-hamster cell fusion and characterization of hybrids by cytogenetic and isozymic techniques. Studies on regulation of these pathways will be extended to include normal human cells and cells from age-related disease conditions such as Werner's Syndrome, Progeria, and Alzheimer's Syndrome. The information gained in understanding the regulation of these two pathways should be important in the understanding of normal and abnormal processes in humans, including the functioning of the immune system, malignancy, and aging.